DeMent was born near Paragould, Arkansas, the youngest child of Pat DeMent and his second wife, Flora Mae. As the baby of the family, she was Pat DeMent's 14th child, and Flora Mae's eighth. Iris's mother had harbored dreams of going to Nashville and starting a singing career. Although she put those plans on hold to get married, her singing voice was an inspiration and influence for her youngest daughter Iris.[1] DeMent was raised in a Pentecostal household. Her family moved from Arkansas to the Los Angeles area when she was three. While growing up, she was exposed to and influenced by country and gospel music.[2] Singing at age five as one of "the little DeMent sisters", Iris had a bad experience when she forgot her words during her first performance, which caused her to avoid performing in public for some time.[1]

DeMent was inspired to write her first song "Our Town" by a drive through a boarded-up Midwest town, at the age of 25.[1] The song lyrics came to her "exactly as it is now", without need for re-writing, and she realized then that songwriting was her calling in life.[1] "Our Town" was played during the closing scene for the final episode (July 26, 1995) of CBS's television series Northern Exposure. The song has been recorded by Kate Brislin and Jody Stecher.

Her first album, Infamous Angel, was released in 1992 on the Rounder-Philo label and explored such themes as religious skepticism, small-town life, and human frailty. "Let the Mystery Be" has been covered by a number of artists, including 10,000 Maniacs and Alice Stuart, and was used in the opening scenes of the film Little Buddha. In the fall of 2015, a version of "Let the Mystery Be" from the Transatlantic Sessions became the musical theme for the opening credits of the HBO series The Leftovers, replacing the original "Main Title Theme" composed by Max Richter, and it would once again serve as the opening theme for the series finale.

In her second album, My Life, released in 1994, she continued the personal and introspective approach. The record is dedicated to her father, who died two years earlier. My Life was nominated for a Grammy Award in the Best Contemporary Folk Album category.[3]

DeMent's third album, The Way I Should, was released in 1996. Featuring the protest song "Wasteland of the Free", it is DeMent's most political work. It covers topics such as sexual abuse, religion, government policy, and Vietnam.[4]

She sang four duets with John Prine on his 1999 album In Spite of Ourselves, including the title track.[5] She appeared in the 2000 film Songcatcher, playing the character Rose Gentry and singing on the soundtrack as well. Her duet with Ralph Stanley on "Ridin' That Midnight Train" was the opening track on his 2001 album, Clinch Mountain Sweethearts: Ralph Stanley & Friends.[6]

In 2004 she released Lifeline, an album of gospel songs. It included 12 covers and one original composition ("He Reached Down").[7] A shortened version of her rendition of "Leaning on the Everlasting Arms" was later used in the closing credits of the Coen brothers' film True Grit. On October 2, 2012, DeMent released her first album of original songs in 16 years, Sing the Delta.[8]

In 2015, DeMent released The Trackless Woods an album based upon and inspired by the words of Russian poet, Anna Akhmatova on her own Flariella record label. She reunited with John Prine in 2016 for his second duets album For Better, or Worse and performed on two tracks. DeMent will receive the Americana Trailblazer Award at the 2017 Americana Music Honors & Awards.